The unique feature of glycoproteins encoded by the Major Histocompatibility Complex (MHC) is their extensive polymorphism. This property led to their description as a system of alloantigens and to the discovery of their key biological function in antigen recognition by T lymphocytes. The class I MHC antigens of man, HLA-A,B,C offer an excellent system for detailed analysis because a large number of molecules from an outbred population are serologically characterized and because determination of acrystallographic structure is in progress. At present ten sequences for HLA-A,B,C products have ben obtained and from their comparison it is clear that more sequences from a wider range of molecules are required to provide an understanding of the nature of MHC polymorphism and its immunological consequences. We have developed streamlined procedures for isolating HLA-A,B genes, identifying their products and sequencing the protein encoding exons. We propose to obtain the sequences of a minimum of twenty HLA-A,B molecules. Results from two families of molecules focused on HLA-A2 and HLA-B7 will provide detailed information on the nature of polymorphic epitopes recognized by antibodies and cytotoxic T lymphocytes and their relationship to sequence variability, and three dimensional structure. Sequences from these pairs of B locus molecules and one A locus molecule will establish the molecular basis for the Bw4 and Bw6 epitopes and provide clues as to their diallelism, frequency and unusual distribution. We hypothesize they represent a "hot spot" for gene conversion events. Additional HLA-A,B molecules covering all the major cross reacting groups will be sequenced in order to provide a representative data set for a general comparison of a statistically significant number of sequences. This analysis will determine the organization and magnitude of polymorphic variation. Variation in A and B locu molecules will be compared. We shall critically assess whether regions of hypervariability exist and how the variability compares with that of immunoglobulins, class II MHC molecules and T cell receptors. An exhaustive pairwise comparison of molecules will generate a set of evolutionary relationshps, reveal mutational hot spots and allow the contribution of various genetic mechanism to variability to be assessed.